Malignant hyperthermia is a pharmacogenetic disease in man and pigs which predisposes to a catastrophic, often fatal syndrome during general anesthesia. The syndrome may also be induced by stressors in susceptible pigs and a possible role of stress for MH in man has been suggested. A common feature for MH susceptible man and pigs is the existence of abnormal in vitro metabolic and contracture responses of skeletal muscle to various drugs, especially to certain anesthetic agents. The working hypothesis of this proposal is that these abnormal metabolic and contracture responses of MH muscle represent the primary etiologic event in the MH syndrome and that these are the consequence of a sustained increase in myoplasmic Ca++. Furthermore, it is proposed that the anesthetic agents that trigger MH do so by acting on skeletal membranes to cause the abnormal increase in myoplasmic Ca++. This project will investigate biochemical and pharmacologic properties of Ca++ uptake and release by skeletal sarcoplasmic reticulum (SR) isolated from muscle of human patients referred for MH diagnostic screening, and from pigs with varying diagnostic contracture phenotypes. The relationships among contracture phenotype, MH susceptibility and SR function will be explored. A noninvasive test for measuring electromechanical coupling and contraction/relaxation kinetics in skeletal muscle will be evaluated in MH diagnostic patients and in pigs with varying contracture phenotypes. These tests will be evaluated for diagnostic and etiologic potential for MH susceptible skeletal muscle. The information obtained will provide a basis for understanding the pathogenesis, form a diagnostic base, and give rationale for prevention and/or treatment of malignant hyperthermia during general anesthesia.